During the past decade, many nucleoside analogs have been found to exhibit good antitumor and antiviral activities. Among the presently known synthetic nucleosidic antiviral agents, the more important are generally considered to be 5'-iodo-2'-deoxyuridine (IDU); 9-.beta.-D-arabinofuranosyladenine (Ara-A); and 1-.beta.-D-arabinofuranosylcytosine (Ara-C). Of these compounds, only IDU is commercially available specifically as an antiviral agent, and this compound has extremely low solubility, i.e., a maximum solubility of about 0.1 weight percent, and is also highly toxic. Ara-A presently is undergoing clinical testing as an antiviral agent, and while the reported evidence suggests that Ara-A is an effective agent against a spectrum of virus infections, its utility is severely limited by its low solubility, and by human toxic symptoms which include mild nausea, transient leukopenia and central nervous system involvement which causes illusions and hallucinations.
When nucleosidic analogs are used to inhibit viral growth, the nucleosides are usually metabolized in vivo to their corresponding mono or poly phosphates which are the actual inhibitors of such growth. A major obstacle in the use of nucleoside analogs in chemotherapy has been the emergence of cellular resistance whereby such compounds are degraded to a form where they may be less effective inhibitors. It is accordingly desirable to have nucleosidic analogs which are capable of effectively inhibiting the development of virus infections and which also possess superior solubility and less toxicity than presently known antiviral agents. The production of such a compound, however, is quite difficult, since relatively few nucleosidic compounds are known which have demonstrated antiviral activity, even in vitro. Moreover, to provide such a compound which has acceptable activity and which is also capable of contacting the virus infection in effective concentrations makes this task exceedingly difficult.
In German Patent Application No. 2,047,368, 9-.beta.-D-arabinofuranosyladenine-5'-phosphate is suggested as a compound useful as an antiviral agent. This compound, however, as an AMP analog and a precursor to an ATP analog is rapidly degraded in the metabolic system (eventually to uric acid). Since ATP levels in the metabolic system are carefully maintained by the metabolic system at low levels the effectiveness of such compounds as antiviral agents is accordingly diminished.
In view of the foregoing, we thus sought to prepare additional nucleosidic analogs in order to investigate the possibilities that certain such compounds might be capable of withstanding rapid metabolic degradation and also penetrating the cellular membrane and contacting virus infections in effective concentrations. As will be apparent from the description which follows, we have synthesized 9-.beta.-D-arabinofuranosylhypoxanthine-5'-phosphate and found such compound to demonstrate marked activity against a spectrum of herpes and other DNA viruses. We have also synthesized other 9-.beta.-D-arabinofuranosyl nucleotides having a phosphorylated arabinoside joined thereto by a glycoside linkage and found that many of them demonstrate marked activity against a spectrum of herpes and other DNA viruses.